Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise.
Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise.
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DOI：
10.1016/j.cmet.2015.06.003
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发表时间：
2015-07-07
期刊：
影响因子：
29
通讯作者：
Muoio DM
中科院分区：
文献类型：
--
作者：
Seiler SE;Koves TR;Gooding JR;Wong KE;Stevens RD;Ilkayeva OR;Wittmann AH;DeBalsi KL;Davies MN;Lindeboom L;Schrauwen P;Schrauwen-Hinderling VB;Muoio DM
酰基肉碱代谢物作为营养胁迫的生物标志物已经引起了人们的关注，但它们的生理相关性和代谢目的仍然知之甚少。短链肉毒碱缀合物，包括乙酰肉毒碱，通过肉毒碱乙酰转移酶（CrAT）（一种双向线粒体基质酶）的作用，从相应的酰基辅酶a前体衍生而来。我们在这里表明，收缩活动逆转了肌肉中的乙酰肉碱通量，从休息时的净生产和流出到运动时的净吸收和消耗。在肌肉特异性CrAT缺乏的小鼠中，这种开关的破坏导致乙酰辅酶a缺陷，能量充电紊乱和运动耐受性降低，而乙酰肉碱补充以CrAT依赖的方式产生相反的结果。同样，与未训练的人相比，运动后磷酸肌酸恢复率与CrAT活性呈正相关，并与肌肉乙酰肉碱动力学的急剧变化相吻合。这些发现表明，乙酰肉碱是工作肌肉的关键乙酰缓冲剂，并为对抗运动不耐受的潜在治疗策略提供了见解。
Acylcarnitine metabolites have gained attention as biomarkers of nutrient stress, but their physiological relevance and metabolic purpose remain poorly understood. Short chain carnitine conjugates, including acetylcarnitine, derive from their corresponding acyl-CoA precursors via the action of carnitine acetyltransferase (CrAT), a bidirectional mitochondrial matrix enzyme. We show here that contractile activity reverses acetylcarnitine flux in muscle, from net production and efflux at rest to net uptake and consumption during exercise. Disruption of this switch in mice with muscle-specific CrAT deficiency resulted in acetyl-CoA deficit, perturbed energy charge and diminished exercise tolerance, whereas acetylcarnitine supplementation produced opposite outcomes in a CrAT-dependent manner. Likewise, in exercise-trained compared to untrained humans, post-exercise phosphocreatine recovery rates were positively associated with CrAT activity and coincided with dramatic shifts in muscle acetylcarnitine dynamics. These findings show acetylcarnitine serves as a critical acetyl buffer for working muscles and provide insight into potential therapeutic strategies for combatting exercise intolerance.